Angiogenesis and Metastasis-Program 4 Sphingosine lipids are complex molecules which are components of both human and animal tissues, as well as prominent components of plants. These molecules are composed of sphingoid base backbone to which is attached a fatty acid acyl backbone, and a phosphodiester or glycosyl- linked headgroup. These molecules may have mitotic or anti-mitotic activity due to differential metabolism of precursors or due to differences in the lipid core. For instance, sphingosine is pro-apoptotic and anti- mitotic, while sphingosine-1 phosphate has a pro-mitotic dominant oncogenes or loss of tumor suppressor genes, and may contribute to the angiogenic and metastatic phenotype in cancer. Alternatively, interference with sphingosine metabolism may prevent primary tumors from becoming angiogenic and metastatic. Specific Aim #1: We will determine whether sphingosine metabolism, namely conversion of sphingosine to sphingosine-1 phosphate is affected by oncogenic ras. Specific Aim #3: We will determine the relative potency and endothelial specificity of sphingosine analogs in inhibition of MAP kinase and P-I-3 kinase signaling through a high throughput screen in immortalized (MS1) and transformed (SVR) endothelial cells. Specific Aim #2: We will determine whether sphingosine-1 phosphate affects the angiogenic switch in endothelial cells and radial growth melanoma cells. Specific Aim #3.: We will determine the relative potency and endothelial specificity of sphingosine analogs in inhibition of MAP kinase and P-I-3 kinase signaling through a high throughput screen in immortalized (MS1) and transformed (SVR) endothelial cells. These studies will assist in the development of novel therapeutics and dietary modifications which may be of use in the prevention and treatment of malignant disease.